Psychosine, the cytotoxic sphingolipid that accumulates in globoid cell leukodystrophy, alters membrane architecture.

[krabbe disease]

Globoid cell leukodystrophy (GLD ) is a neurological disease caused by deficiency of the lysosomal enzyme galactosylceramidase (GALC ). In the absence of GALC , the cytotoxic glycosphingolipid , psychosine (psy ), accumulates in the nervous system . Psychosine accumulation preferentially affects oligodendrocytes , leading to progressive demyelination and infiltration of activated monocytes /macrophages into the CNS . GLD is characterized by motor defects , cognitive deficits , seizures , and death by 2 -5 years of age . It has been hypothesized that psychosine accumulation , primarily within lipid rafts , results in the pathogenic cascade in GLD . However , the mechanism of psychosine toxicity has yet to be elucidated . Therefore , we synthesized the enantiomer of psychosine (ent-psy ) to use as a probe to distinguish between protein-psy (stereo-specific enantioselective ) or membrane-psy (stereo-insensitive nonenantioselective ) interactions . The enantiomer of psychosine has equal or greater toxicity compared with psy , suggesting that psy exerts its toxicity through a nonenantioselective mechanism . Finally , in this study we demonstrate that psy and ent-psy localize to lipid rafts , perturb natural and artificial membrane integrity , and inhibit protein Kinase C translocation to the plasma membrane . Although other mechanisms may play a role in disease , these data strongly suggest that psy exerts its effects primarily through membrane perturbation rather than through specific protein-psy interactions .

Diseases
Validation

Diseases presenting "seizures" symptom

alexander disease

alpha-thalassemia

cadasil

canavan disease

child syndrome

classical phenylketonuria

coats disease

cohen syndrome

cowden syndrome

erdheim-chester disease

familial hypocalciuric hypercalcemia

familial mediterranean fever

gm1 gangliosidosis

hirschsprung disease

homocystinuria without methylmalonic aciduria

kabuki syndrome

kallmann syndrome

krabbe disease

lamellar ichthyosis

legionellosis

locked-in syndrome

lymphangioleiomyomatosis

malignant atrophic papulosis

monosomy 21

neonatal adrenoleukodystrophy

oligodontia

phenylketonuria

proteus syndrome

pyruvate dehydrogenase deficiency

scrub typhus

sneddon syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

This symptom has already been validated